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1.
Front Immunol ; 11: 573662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123152

RESUMO

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.


Assuntos
Senescência Celular/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Envelhecimento/imunologia , Betacoronavirus/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Monócitos/imunologia , Neutrófilos/imunologia , Obesidade/imunologia , Pandemias , Fatores de Risco , Linfócitos T/imunologia
2.
Nat Commun ; 11(1): 5061, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033262

RESUMO

The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3's catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.


Assuntos
Reprogramação Celular , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Animais , Catálise , Proliferação de Células , Senescência Celular , Desmetilação , Elementos Facilitadores Genéticos/genética , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Histonas/metabolismo , Lisina/metabolismo , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ativação Transcricional/genética
3.
Einstein (Sao Paulo) ; 18: eAO5236, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33084793

RESUMO

OBJECTIVE: To follow the expansion of mesenchymal stem cells from umbilical cords by two classic senescence markers, p16 (INK4A) and p21 (CDKN1A), using practical, fast, and less expensive methods than the gold standard Western blotting technique, to evaluate its applicability in the laboratory. METHODS: Mesenchymal stem cells from umbilical cords were isolated from Wharton's jelly and, after quality control, morphological and immunophenotypic characterization by flow cytometry, were expanded in culture until coming close to cell cycle arrest (replicative senescence). RESULTS: A comparison was made between young cells, at passage 5, and pre-senescent cells, at passage 10, evaluating the protein expression of the classic cell senescence markers p16 and p21, comparing the results obtained by Western blotting with those obtained by flow cytometry and indirect immunofluorescence. CONCLUSION: Follow-up of cell cultures, through indirect p16 immunofluorescence, allows the identification of mesenchymal stem cells from umbilical cord cultures at risk of reaching replicative senescence.


Assuntos
Senescência Celular , Citometria de Fluxo/métodos , Imunofluorescência/métodos , Células-Tronco Mesenquimais/fisiologia , Cordão Umbilical/fisiologia , Biomarcadores/sangue , Western Blotting , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Humanos
4.
Nucleic Acids Res ; 48(19): 11083-11096, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33035345

RESUMO

N6-Methyladenosine (m6A) messenger RNA methylation is a well-known epitranscriptional regulatory mechanism affecting central biological processes, but its function in human cellular senescence remains uninvestigated. Here, we found that levels of both m6A RNA methylation and the methyltransferase METTL3 were reduced in prematurely senescent human mesenchymal stem cell (hMSC) models of progeroid syndromes. Transcriptional profiling of m6A modifications further identified MIS12, for which m6A modifications were reduced in both prematurely senescent hMSCs and METTL3-deficient hMSCs. Knockout of METTL3 accelerated hMSC senescence whereas overexpression of METTL3 rescued the senescent phenotypes. Mechanistically, loss of m6A modifications accelerated the turnover and decreased the expression of MIS12 mRNA while knockout of MIS12 accelerated cellular senescence. Furthermore, m6A reader IGF2BP2 was identified as a key player in recognizing and stabilizing m6A-modified MIS12 mRNA. Taken together, we discovered that METTL3 alleviates hMSC senescence through m6A modification-dependent stabilization of the MIS12 transcript, representing a novel epitranscriptional mechanism in premature stem cell senescence.


Assuntos
Adenosina/análogos & derivados , Metiltransferases/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Progéria/genética , RNA Mensageiro/metabolismo , Síndrome de Werner/genética , Adenosina/genética , Células Cultivadas , Senescência Celular , Humanos , Células-Tronco Mesenquimais , Metilação , Proteínas de Ligação a RNA/metabolismo
5.
Nucleic Acids Res ; 48(19): 10909-10923, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33045748

RESUMO

The three-dimensional configuration of the chromatin architecture is known to be crucial for alterations in the transcriptional network; however, the underlying mechanisms of epigenetic control of senescence-related gene expression by modulating the chromatin architecture remain unknown. Here, we demonstrate frequent chromosomal compartment switching during mouse embryonic fibroblasts (MEFs) replicative senescence as characterized by senescence-inactivated (SIAEs) and -activated enhancers (SAEs) in topologically associated domains (TADs). Mechanistically, SAEs are closely correlated with senescence-associated secretory phenotype (SASP) genes, which are a key transcriptional feature of an aging microenvironment that contributes to tumor progression, aging acceleration, and immunoinflammatory responses. Moreover, SAEs can positively regulate robust changes in SASP expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is capable of enhancing SAE activity, which accelerates the emergence of SAEs flanking SASPs and the secretion of downstream factors, contributing to the progression of senescence. Our results provide novel insight into the TAD-related control of SASP gene expression by revealing hierarchical roles of the chromatin architecture, transcription factors, and enhancer activity in the regulation of cellular senescence.


Assuntos
Envelhecimento/genética , Senescência Celular , Fibroblastos/citologia , Regulação da Expressão Gênica , Animais , Células Cultivadas , Cromatina/metabolismo , Embrião de Mamíferos , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Sequências Reguladoras de Ácido Nucleico
6.
Nat Commun ; 11(1): 4979, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020468

RESUMO

Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. However, the mechanisms and factors that control the negative effects of senescence while retaining its benefits are still elusive. Here, we show that the rasGAP SH3-binding protein 1 (G3BP1) is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.


Assuntos
Senescência Celular/fisiologia , DNA Helicases/metabolismo , Neoplasias/patologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Células A549 , Animais , Carcinogênese , Linhagem Celular , Movimento Celular , Citocinas/metabolismo , DNA Helicases/antagonistas & inibidores , DNA Helicases/deficiência , Humanos , Inflamação , Camundongos , Neoplasias/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/deficiência , RNA Helicases/antagonistas & inibidores , RNA Helicases/deficiência , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/deficiência , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo
8.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32953088

RESUMO

Obesity and osteoporosis are both common conditions with high rates of morbidity and mortality. There is a relationship between obesity and bone. There are multiple factors that influence the risk of fracture, including the quality of bone, the risk of falls, and the padding around the bone. These multiple factors partly explain the finding that obesity protects against fractures in some sites while increasing the risk in other parts of the body. While it is well known that increased weight builds bone, there are several mechanisms related to the obese state that make the bone more fragile. These include the increased production of bone marrow fat cells at the expense of bone-forming osteoblasts, an increase in inflammatory cytokines leading to the activation of bone-resorbing osteoclasts, mutations in the FTO gene, and obesity-induced increased osteoblast senescence. Surprisingly, the relationship between bone and obesity is not unidirectional; there is now evidence that osteocytes are able to regulate body weight by acting as weighing machines.


Assuntos
Osso e Ossos/patologia , Obesidade/fisiopatologia , Osteoblastos/citologia , Osteoclastos/citologia , Osteócitos/citologia , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Senescência Celular , Humanos
9.
Cell Prolif ; 53(10): e12894, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32881115

RESUMO

Cancer is the principal cause of death and a dominant public health problem which seriously threatening human life. Among various ways to treat cancer, traditional Chinese medicine (TCM) and natural products have outstanding anti-cancer effects with their unique advantages of high efficiency and minimal side effects. Cell senescence is a physiological process of cell growth stagnation triggered by stress, which is an important line of defence against tumour development. In recent years, active ingredients of TCM and natural products, as an interesting research hotspot, can induce cell senescence to suppress the occurrence and development of tumours, by inhibiting telomerase activity, triggering DNA damage, inducing SASP, and activating or inactivating oncogenes. In this paper, the recent research progress on the main compounds derived from TCM and natural products that play anti-cancer roles by inducing cell senescence is systematically reviewed, aiming to provide a reference for the clinical treatment of pro-senescent cancer.


Assuntos
Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Alcaloides/química , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Senescência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Medicina Tradicional Chinesa , Neoplasias/patologia , Fenóis/química , Fenóis/farmacologia , Fenóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
11.
Aging Cell ; 19(10): e13237, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32955770

RESUMO

SARS-CoV-2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID-19), a complex respiratory distress syndrome. Epidemiological data show that COVID-19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association between SARS-CoV-2 infection and the process of biological aging may provide a tractable avenue for therapy to prevent acute and long-term disease. Here, we discuss how cellular senescence-a state of stable growth arrest characterized by pro-inflammatory and pro-disease functions-can hypothetically be a contributor to COVID-19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity. First, we define why older COVID-19 patients are more likely to accumulate high levels of cellular senescence. Second, we describe how senescent cells can contribute to an uncontrolled SARS-CoV-2-mediated cytokine storm and an excessive inflammatory reaction during the early phase of the disease. Third, we discuss the various mechanisms by which senescent cells promote tissue damage leading to lung failure and multi-tissue dysfunctions. Fourth, we argue that a high senescence burst might negatively impact on vaccine efficacy. Measuring the burst of cellular senescence could hypothetically serve as a predictor of COVID-19 severity, and targeting senescence-associated mechanisms prior and after SARS-CoV-2 infection might have the potential to limit a number of severe damages and to improve the efficacy of vaccinations.


Assuntos
Envelhecimento/imunologia , Senescência Celular/imunologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Fatores Etários , Idoso , Betacoronavirus , Biomarcadores/análise , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Pneumonia Viral/mortalidade , Índice de Gravidade de Doença
12.
Chem Biol Interact ; 331: 109250, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956706

RESUMO

Triple-negative breast cancer is the most aggressive form of breast cancer with limited intervention options. Moreover, a number of belligerent therapeutic strategies adopted to treat such aggressive forms of cancer have demonstrated detrimental side effects. This necessitates exploration of targeted chemotherapeutics. We assessed the efficacy of a novel indenone derivative (nID) [(±)-N-(2-(-5-methoxy-1-oxo-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-inden-2-yl)ethyl)-4-methylbenzenesulfonamide], synthesized by a novel internal nucleophile-assisted palladium-catalyzed hydration-olefin insertion cascade; against triple-negative breast cancer cells (MDA-MB-231). On 24 h treatment, the nID caused decline in the viability of MDA-MB-231 and MDA-MB-468 cells, but did not significantly (P < 0.05) affect WRL-68 (epithelial-like) cells. In fact, the nID demonstrated augmentation of p53 expression, and consequent p53-dependent senescence in both MDA-MB-231 and MDA-MB-468 cells, but not in WRL-68 cells. The breast cancer cells also exhibited reduced proliferation, downregulated p65/NF-κB and survivin, along with augmented p21Cip1/WAF1 expression, on treatment with the nID. This ensued cell cycle arrest at G1 stage, which might have driven the MDA-MB-231 cells to senescence. We observed a selectivity of the nID to target MDA-MB-231 cells, whereas WRL-68 cells did not show any considerable effect. The results underscored that the nID has potential to be developed into a cancer therapeutic.


Assuntos
Antineoplásicos/síntese química , Senescência Celular , Sulfonamidas/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Catálise , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Paládio/química , Sulfonamidas/síntese química , Survivina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
13.
Mol Cell Biol ; 40(22)2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-32900821

RESUMO

The rRNA gene, which consists of tandem repetitive arrays (ribosomal DNA [rDNA] repeat), is one of the most unstable regions in the genome. The rDNA repeat in the budding yeast Saccharomyces cerevisiae is known to become unstable as the cell ages. However, it is unclear how the rDNA repeat changes in aging mammalian cells. Using quantitative single-cell analyses, we identified age-dependent alterations in rDNA copy number and levels of methylation in mice. The degree of methylation and copy number of rDNA from bone marrow cells of 2-year-old mice were increased by comparison to levels in 4-week-old mice in two mouse strains, BALB/cA and C57BL/6. Moreover, the level of pre-rRNA transcripts was reduced in older BALB/cA mice. We also identified many sequence variations in the rDNA. Among them, three mutations were unique to old mice, and two of them were found in the conserved region in budding yeast. We established yeast strains with the old-mouse-specific mutations and found that they shortened the life span of the cells. Our findings suggest that rDNA is also fragile in mammalian cells and that alterations within this region have a profound effect on cellular function.


Assuntos
Envelhecimento/genética , Variações do Número de Cópias de DNA , Metilação de DNA , DNA Ribossômico/metabolismo , Envelhecimento/metabolismo , Animais , Células da Medula Óssea/metabolismo , Senescência Celular/genética , Sequência Conservada , Análise Mutacional de DNA , Sequência de DNA Instável , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Saccharomycetales/genética , Análise de Célula Única , Especificidade da Espécie , Transcrição Genética
14.
Ann Hematol ; 99(10): 2265-2277, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32803313

RESUMO

ß-Thalassemia is an inherited single gene disorder related to reduced synthesis of the ß-globin chain of hemoglobin. Patients with ß-thalassemia present variable clinical severity ranging from asymptomatic trait to severe transfusion-dependent anemia and multiple organs complications. Moreover, multiple immune abnormalities are a major concern in ß-thalassemia patients. Aberrant neutrophil effector function plays a pivotal role in infection susceptibility in these patients. In severe and persistent inflammation, immature neutrophils are released from the bone marrow and are functionally different compared with mature ones. Despite some abnormalities reported for thalassemia patient's immune system, few data exist on the characterization of human neutrophils in ß-thalassemia. The aim of this study was to investigate the phenotype and function of circulating neutrophil subsets in patients with ß-thalassemia major and with ß-thalassemia intermedia divided in transfusion-dependent and non-transfusion-dependent. By the use of immunochemical and cytofluorimetric analyses, we observed that patients' CD16+ neutrophils exhibit abnormalities in their phenotype and functions and the abnormalities vary according to the clinical form of the disease and to the neutrophil subset (CD16bright and CD16dim). Abnormalities include altered surface expression of the innate immune receptor CD45, Toll-like receptor 4, and CD32, reduced ability to produce an oxidative burst, and elevated levels of membrane lipid peroxidation, especially in patients with a more severe form of the disease. Overall, our results indicating the occurrence of an immuno-senescent phenotype on circulating neutrophils from thalassemia patients suggest the usefulness of neutrophil feature assessment as a tool for better clinical management of ß-thalassemia.


Assuntos
Neutrófilos/imunologia , Talassemia beta/sangue , Adulto , Antígenos CD/sangue , Transfusão de Componentes Sanguíneos , Senescência Celular , Terapia por Quelação , Feminino , Ferritinas/sangue , Humanos , Imunofenotipagem , Quelantes de Ferro/uso terapêutico , Contagem de Leucócitos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo , Neutrófilos/química , Neutrófilos/classificação , Explosão Respiratória , Esplenectomia , Receptor 4 Toll-Like/sangue , Adulto Jovem , Talassemia beta/imunologia , Talassemia beta/terapia
15.
Science ; 369(6506)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820093

RESUMO

In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.


Assuntos
Envelhecimento/patologia , Retinopatia Diabética/patologia , Armadilhas Extracelulares/imunologia , Vasos Retinianos/patologia , Animais , Senescência Celular , Retinopatia Diabética/imunologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Vasos Retinianos/imunologia
16.
PLoS Biol ; 18(8): e3000808, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817651

RESUMO

Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.


Assuntos
Aneurisma da Aorta Abdominal/genética , Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Mitocôndrias/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Idoso , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Senescência Celular/efeitos dos fármacos , Ecocardiografia , Células Endoteliais/patologia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/deficiência , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
17.
Nat Commun ; 11(1): 4289, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855397

RESUMO

Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.


Assuntos
DNA Mitocondrial/efeitos adversos , Dasatinibe/farmacologia , Inflamação/prevenção & controle , Transplante de Órgãos/métodos , Quercetina/farmacologia , Adulto , Envelhecimento/fisiologia , Animais , Diferenciação Celular , Ácidos Nucleicos Livres , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Citocinas/metabolismo , DNA Mitocondrial/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Humanos , Inflamação/etiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Doadores de Tecidos
18.
Sheng Li Xue Bao ; 72(4): 426-432, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32820304

RESUMO

The purpose of the present study was to investigate the effects of forkhead box O4 (FOXO4) on the senescence of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The hUC-MSCs were induced to senescence by natural passage, and FOXO4 expression was inhibited by lentiviral shRNA transfection. The hallmark of cell senescence was analyzed by ß-galactosidase staining, and the cell viability was assayed by CCK-8 method. Flow cytometry was used to investigate the apoptosis of hUC-MSCs. The expression levels of Bcl-2, Bax, FOXO4, interleukin 6 (IL-6) and cleaved Caspase-3 were detected by qPCR and Western blot. Immunofluorescence staining was used to detect FOXO4 expression. The amount of IL-6 secreted by hUC-MSCs was detected by ELISA. The results showed that, compared with the passage 1, senescent hUC-MSCs showed up-regulated expression levels of Bax and FOXO4, down-regulated expression levels of Bcl-2 and cleaved Caspase-3, and increased IL-6 mRNA expression and secretion. FOXO4 inhibition in senescent hUC-MSCs promoted cell apoptosis, reduced cell viability, and inhibited the mRNA expression and secretion of IL-6. These results suggest that FOXO4 maintains viability and function of senescent hUC-MSCs by repressing their apoptosis response, thus accelerating senescence of the whole cell colony.


Assuntos
Apoptose , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Proteínas de Ciclo Celular , Sobrevivência Celular , Senescência Celular , Fatores de Transcrição Forkhead , Humanos , Fatores de Transcrição , Cordão Umbilical
19.
Mol Ecol ; 29(16): 2951-2953, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745307

RESUMO

The relationship of telomere shortening and cellular ageing in cultured cells such as fibroblasts is straightforward: telomeres shorten with an increasing number of cell divisions until they trigger replicative senescence which prevents further mitotic cycles. But studies investigating the relationship between telomere shortening and ageing in whole organisms show contrasting results: while there is a clear decline in telomere length (TL) with chronological age in some species such as humans, no such decline is observed in others. In this issue of Molecular Ecology, Foley et al. (2020) show that experiencing harsh weather conditions correlates with longitudinal telomere shortening in the bat species Myotis myotis, whereas chronological age does not (Foley et al., 2020). Further, the authors investigated whether genetics influence TL and find a low heritability (h2  = 0.01-0.06) again suggesting that environmental effects are the dominant drivers of variation in TL in this species. These are important findings as there is disagreement in the literature about the relative magnitude of genetic and environmental effects contributing to TL variation in different species. This paper investigating the impact of environmental effects makes a novel and important contribution to the literature on TL in free-living mammals.


Assuntos
Quirópteros , Encurtamento do Telômero , Animais , Senescência Celular , Quirópteros/genética , Humanos , Telômero/genética , Tempo (Meteorologia)
20.
Ecotoxicol Environ Saf ; 204: 111070, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32763567

RESUMO

Silver nanoparticles (AgNPs) are widely used as antimicrobial agents and resulted in their accumulation in environment. The purpose of this study was to investigate the detailed molecular mechanisms underlying AgNP-induced lung cellular senescence which has been proposed as a pathogenic driver of chronic lung disease. Herein, we demonstrate that exposure to AgNPs elevates multiple senescence biomarkers in lung cells, with cell cycle arrest in the G2/M phase, and potently activates genes of the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cell line MRC5. Fluorescence-based assay also reveals that apoptosis induced by AgNPs is associated with senescence. Furthermore, we show that AgNPs cause premature senescence through an increase in transcription factor nuclear factor kappa B (NF-κB), cyclooxygenase-2 (COX2) expression and over-production of prostaglandin E2 (PGE2) in lung cells. Inhibition of COX2 reduces AgNPs-induced senescence to a normal level. Moreover, AgNPs also induce upregulation of COX2 and accelerate lung cellular senescence in vivo and cause mild fibrosis in the lung tissue of mice. Taken together, our studies support a critical role of AgNPs in the induction of lung cellular senescence via the upregulation of the COX2/PGE2 intracrine pathway, and suggest the adverse effects to the human respiratory system.


Assuntos
Senescência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Prata/metabolismo
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